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Abstract

We present a case of a 62-year-old man who underwent total hip arthroplasty for treatment
of pathologic femoral neck fracture associated with adefovir dipivoxil-induced osteomalacia.
He had a 13-month history of bone pain involving his shoulders, hips, and knee. He
received adefovir dipivoxil for treatment of lamivudine-resistant hepatitis B virus
infection for 5 years before the occurrence of femoral neck fracture. Orthopedic surgeons
should be aware of osteomalacia and pathological hip fracture caused by drug-induced
renal dysfunction, which results in Fanconi’s syndrome.

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Keywords:

Background

Hypophosphatemic osteomalacia caused by proximal renal tubule dysfunction induces
Fanconi’s syndrome, which leads to impaired reabsorption of amino acids, glucose,
urate, and phosphate [1]. The chronic loss of phosphate and impaired synthesis of 1,25-dihydroxyvitamin D3
may lead to failure of bone mineralization. Recently, osteomalacia was reported in
cases in which hepatitis B virus and human immunodeficiency virus (HIV) infections
were treated using high-dose adefovir dipivoxil [2-6]. We report a case of a patient who underwent total hip arthroplasty for pathological
femoral neck fracture associated with osteomalacia induced by low-dose adefovir dipivoxil
treatment.

Case presentation

A 62-year-old man started experiencing pain in the right knee and left shoulder pain
in January 2010. He visited a clinic and was administered salazosulfapyridine and
methylprednisolone therapy for rheumatoid arthritis. However, the pain gradually increased,
and he started experiencing pain in his hip joints as well. Therefore, he was admitted
our hospital for further examination in February 2011. He had a 7-year history of
chronic hepatitis caused by hepatitis B virus infection, and had received lamivudine
therapy for 2 years. Because the virus developed resistance to lamivudine, he received
adefovir dipivoxil for 5 years before the development of the femoral neck fracture.
After adefovir dipivoxil treatment, his liver function was restored. Radiography showed
femoral neck fractures (right, Garden III fracture; left, Garden IV fracture) and
a distal right tibial fracture (Figure 1a) [7]. Magnetic resonance imaging (MRI) of both hip joints showed fractures across the
right and left femoral neck and bone edema, which had low intensity on T1-weighted
images and high intensity on T2-weighted images (Figure 1b). 99mTc-hydroxymethylene diphosphonate (HMDP) whole-body bone scintigraphy showed increased
uptake of the radiotracer in the calvaria, maxilla, both scapulae, ribs, both femoral
necks, right condyle of the femur, right tibia, and both tarsi (Figure 1c). He showed hypophosphatemia (2.0 mg/dL; normal range, 2.5–4.5 mg/dL) and increased
levels of alkaline phosphatase (ALP, 1594 IU/L; normal range, 115–359 IU/L). Furthermore,
he showed normal serum creatinine (0.7 mg/dL; normal range, 0.4–0.7 mg/dL), blood
urea nitrogen (BUN, 12.3 mg/dL; normal range, 8.0–22.0 mg/dL), intact parathyroid
hormone (PTH, 19 pg/mL; normal range, 10–65 pg/mL), and 1,25-dihydroxyvitamin D3 (40.0 pg/mL;
normal range, 20–60 pg/mL) levels. Urinalysis revealed proteinuria. A 24-h study showed
increased urinary excretion of phosphate (1004 mg/day; normal range, 70–220 mg/day),
calcium (471.0 mg/day; normal range, 100–300 mg/day), N-acetylglucosaminidase (11.8 U/L; normal range, <7.0 U/L), and β2-microglobulin (64,579 μg/L;
normal range, 230 μg/L). These findings indicated hypophosphatemia and hyperphosphaturia
(increased levels of ALP). However, because the patient had normal levels of 1,25-dihydroxyvitamin
D3, we considered that the impaired phosphate reabsorption could have been caused
by dysfunction of the proximal renal tubule dysfunction and not by deficiency of vitamin
D. Urinalysis and examination of urine samples collected over 24 h showed increased
levels of N-acetylglucosaminidase and β2-microglobulin as well as phosphate wasting, which also
indicated that these symptoms were caused by dysfunction of the proximal renal tubule.

On the basis of these findings, we made a diagnosis of osteomalacia and pathologic
fractures due to Fanconi’s syndrome secondary to adefovir therapy (10 mg/day). We
conducted preoperative examinations to perform total hip arthroplasty. Prolonged bleeding
time was observed by platelet aggregation failure and coagulation factor deficiency
(Table 1). The coagulation disorder was suggested to have been caused by chronic hepatitis.
The bleeding time was normalized by platelet transfusion. or double-labeling analysis,
1000 mg of tetracycline was orally administered at 10-day intervals. A 2-step procedure
was performed under the same general anesthetic. During the first part of the procedure,
biopsy of the iliac bone was performed, and during the second stage of the procedure,
total hip arthroplasty was performed using a Zimmer implant (cemented collarless polished
taper. stem, cementless trabecular metal modular acetabular cup, 36-mm head; Figure 1d). Because the acetabular roof bone was too fragile to support the acetabular components,
bone fragment autografts prepared from the left femoral head were transplanted at
the acetabular roof. The patient received intravenous antibiotics for 3 days. On the
first postoperative day, the patient began rehabilitation under the supervision of
a physiotherapist. He began using crutches for ambulation on postoperative day 7,
with progressive weight-bearing as tolerated. The time to full weight-bearing was
3 weeks after the operation. The iliac bone and femoral head samples were fixed and
stained using Villanueva bone stain and Villanueva–Goldner counterstain. The osteoid
volume/mineralized bone volume ratio was 20.7% (average, <10%) and osteoid thickness
was 25.1 μm (average, <12.5 μm; Figure 2a). Examination using tetracycline labeling showed no double-labeling pattern (Figure 2b) [8]. These findings confirmed that the pathological fractures were caused by osteomalacia
(reviewed in [8]). After surgery, adefovir dipivoxil was switched with entecavir hydrate, and eldecalcitol
and alendronate sodium hydrate were administered. These treatments normalized the
blood phosphate level. The Japanese Orthopaedic Association Hip Score for the hip
joints was 73 points at 2 months after surgery. He did not show any new pathological
fractures.

Discussion

Adefovir dipivoxil is a commonly used antiviral agent in the treatment of chronic
hepatitis B or HIV infection [9]. Fanconi’s syndrome has been recognized as a complication of high-dose adefovir dipivoxil
therapy (dose, 60–120 mg/day) in the treatment of HIV infection [10]. Few studies have reported severe hypophosphatemia with 10 mg/day adefovir dipivoxil
therapy [11-14]. In addition, to our knowledge, this is the first report of pathological femoral
neck fracture associated with adefovir dipivoxil-induced osteomalacia treated by total
hip arthroplasty. When orthopaedic surgeons encounter adefovir dipivoxil–treated chronic
hepatitis B patients with pathological hip fractures, the patients’ renal function
and levels of electrolytes, including calcium and phosphorus, should be carefully
monitored.

Fanconi’s syndrome results from dysfunction of the proximal renal tubule, causing
impaired reabsorption of amino acids, urate, bicarbonate, and phosphate and increased
excretion of these solutes into the urine. The pathophysiology of proximal renal tubule
dysfunction is thought to be an increase in the adefovir dipivoxil concentration in
the mitochondria mediated by inhibition of several ATP-dependent transporters [15,16]. Patients with Fanconi’s syndrome show low phosphate levels (because of renal phosphate
loss) and normal levels of calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D,
and PTH and increased ALP levels. Radiography and bone scan showed multiple patterns
of osteomalacia. Our findings were consistent with those in previous reports [17].

Entecavir is more effective than adefovir dipivoxil, with a favorable safety profile
and low incidence of resistance [18]. We switched adefovir dipivoxil with entecavir hydrate as previously reported [19,20]. Entecavir may be a good treatment choice. In addition to adefovir dipivoxil, the
patient received oral administration of lamivudine, rebamipide, rabeprazole sodium,
and methylprednisolone. These drugs may have caused Fanconi’s syndrome. After the
patient’s condition was diagnosed as Fanconi’s syndrome, adefovir dipivoxil was replaced
with entecavir hydrate. Thereafter, the symptoms of Fanconi’s syndrome improved. These
findings suggested that adefovir dipivoxil caused Fanconi’s syndrome and osteomalacia.

Abbreviations

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

MT, YA, and SN were responsible for data collection. TS, YI, and SK, were responsible
for literature search and manuscript preparation. MH, YS, and HK performed microscopic
examinations, and JK performed surgery. All authors have read and approved the final
manuscript.